Psychotic conditions such as schizophrenia and related disorders (e.g. schizoaffective disorder), are complex and heterogeneous diseases of uncertain etiology that afflict approximately 1 to 2% of all populations worldwide. Schizophrenia is characterized as having both "positive symptoms" (hallucinations, delusions, and conceptual disorganization) and "negative symptoms" (apathy, social withdrawal, affect, and poverty of speech). Abnormal activity of the neurotransmitter dopamine is a hallmark of schizophrenia. Dopaminergic activity is reduced in the mesocortical system (resulting in negative symptoms) and is enhanced in the mesolimbic system (resulting in positive or psychotic symptoms). Several other neurotransmitters are involved, including serotonin, glutamate, and GABA.
For many years, schizophrenia was treated with classical antipsychotic drugs, the neuroleptics, that block central dopamine receptors. The neuroleptics are effective for treating the positive symptoms of schizophrenia, but have little or no effect on the negative symptoms. The ability of these drugs to antagonize dopamine receptors correlates with antipsychotic efficacy. Neuroleptic drugs include phenothiazines including aliphatics (e.g., chlorpromazine), piperidines (e.g., thioridazine), and piperazines (e.g., fluphenazine); butyrophenones (e.g., haloperidol); thioxanthenes (e.g., flupenthixol); oxoindoles (e.g., molindone); dibenzoxazepines (e.g., loxapine) and diphenylpiperidines (e.g., pimozide).
Unfortunately, neuroleptics-resistant negative symptoms account for most of the social and vocational disability caused by schizophrenia. Further, neuroleptics cause extrapyramidal symptoms, including rigidity, tremor, bradykinesia (slow movement), and bradyphrenia (slow thought), as well as tardive dyskinesias and dystonias.
The atypical antipsychotics are a different class of antipsychotic drugs which have a different receptor binding profile and effectiveness against the symptoms of schizophrenia. Atypical antipsychotics bind central serotonin2 (5-HT2) receptors in addition to D2 dopamine receptors. Unlike the neuroleptics, they improve negative as well as positive symptoms. They cause minimal extrapyramidal symptoms and rarely cause tardive dyskinesias, akathisia, or acute dystonic reactions.
The first atypical antipsychotic drug approved for the treatment of schizophrenia was clozapine. Clozapine binds D2 dopamine receptor weakly, but has a strong affinity for the 5-HT2A receptor. Clozapine also antagonizes adrenergic, cholinergic, and histaminergic receptors. Clozapine is effective for the treatment of schizophrenia, especially for subjects who do not respond to traditional neuroleptic therapy. Clozapine has been found to be superior to neuroleptics for improving psychotic symptoms, and generally is better tolerated.
The side effects of clozapine, however, present problems for safety and patient compliance. The side effects include sedation, orthostatic hypotension, hypersalivation, lowered seizure threshold and, in particular, agranulocytosis. The incidence of agranulocytosis in patients taking clozapine is about 1-2%. Agranulocytosis is a serious condition characterized by a precipitous drop in the white blood cell count; the seriousness of the condition mandates that white blood cell counts be measured each week for patients taking clozapine. Another patient compliance issue is the relatively short half life of clozapine in vivo, which necessitates multiple doses each day to maintain therapeutic effectiveness.
Fatty acids previously have been conjugated with drugs to help the drugs as conjugates cross the blood brain barrier. For example, DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranched fatty acid that previously has been shown to be unusually effective in crossing the blood brain barrier. When DHA is conjugated to a drug, the entire drug-DHA conjugate is transported across the blood-brain barrier and into the brain.
DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic (lipophilic). DHA is an important constituent of the brain and recently has been approved as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.
Another example of the conjugation of fatty acids to a drug is the attachment of pipotiazine to stearic acid, palmitic acid, enanthic acid, undecylenic acid or 2,2-dimethyl-palmitic acid. Pipotiazine is a drug that acts within the central nervous system. The purpose of conjugating pipotiazine to the fatty acids was to create an oily solution of the drug as a liquid implant for slow release of the drug when injected intramuscularly. The release of the drug appeared to depend on the particular fatty acid selected, and the drug was tested for its activity in the central nervous system.
Lipidic molecules, including the fatty acids, also have been conjugated with drugs to render the conjugates more lipophilic than the drug. In general, increased lipophilicity has been suggested as a mechanism for enhancing intestinal uptake of drugs into the lymphatic system, thereby enhancing the entry of the conjugate into the brain and also thereby avoiding first-pass metabolism of the conjugate in the liver. The type of lipidic molecules employed have included phospholipids, non-naturally occurring branched and unbranched fatty acids, and naturally occurring branched and unbranched fatty acids ranging from as few as 4 carbon atoms to more than 30 carbon atoms. In one instance, enhanced receptor binding activity was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with the phospholipid membrane to act as a distal anchor for the receptor ligand in the membrane microenvironment of the receptor. This increase in potency, however, was not observed when the same lipid derivatives of adenosine receptor antagonists were used, and generalizations thus were not made possible by those studies.